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Arginase deficiency

MedGen UID:
78688
Concept ID:
C0268548
Disease or Syndrome
Synonyms: ARG1 deficiency; Argininemia
SNOMED CT: Deficiency of arginase (23501004); Arginase deficiency (23501004); Argininemia (23501004); Hyperargininemia (23501004); ARGI deficiency (23501004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ARG1 (6q23.2)
 
Monarch Initiative: MONDO:0008814
OMIM®: 207800
Orphanet: ORPHA90

Definition

Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms. [from GeneReviews]

Additional descriptions

From OMIM
Arginase deficiency is an autosomal recessive inborn error of metabolism caused by a defect in the final step in the urea cycle, the hydrolysis of arginine to urea and ornithine. Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency (237300), argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency.  http://www.omim.org/entry/207800
From MedlinePlus Genetics
Arginase deficiency is an inherited disorder that causes the amino acid arginine (a building block of proteins) and ammonia to accumulate gradually in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if levels become too high. The nervous system is especially sensitive to the effects of excess ammonia.

Arginase deficiency usually becomes evident by about the age of 3. It most often appears as stiffness, especially in the legs, caused by abnormal tensing of the muscles (spasticity). Other symptoms may include slower than normal growth, developmental delays and eventual loss of developmental milestones, intellectual disabilities, seizures, tremors, and difficulty with balance and coordination (ataxia). Occasionally, high-protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase in ammonia may lead to episodes of irritability, refusal to eat, and vomiting.

In some affected individuals, the signs and symptoms of arginase deficiency may be less severe and may not appear until later in life.  https://medlineplus.gov/genetics/condition/arginase-deficiency

Clinical features

From HPO
Orotic aciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Diaminoaciduria
MedGen UID:
870260
Concept ID:
C4024698
Disease or Syndrome
An increased urine level of any amino acid carrying two amino groups (Asparagine, glutamine and lysine, cystine, ornithine).
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Micronodular cirrhosis
MedGen UID:
75640
Concept ID:
C0267812
Disease or Syndrome
A type of cirrhosis characterized by the presence of small regenerative nodules.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Portal fibrosis
MedGen UID:
893107
Concept ID:
C3805083
Disease or Syndrome
Fibroblast proliferation and fiber expansion from the portal areas to the lobule.
Anorexia
MedGen UID:
315
Concept ID:
C0003123
Disease or Syndrome
Anorexia, or the loss of appetite for food, is a medical condition.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
Spastic gait
MedGen UID:
115907
Concept ID:
C0231687
Finding
Spasticity is manifested by increased stretch reflex which is intensified with movement velocity. This results in excessive and inappropriate muscle activation which can contribute to muscle hypertonia. Spastic gait is characterized by manifestations such as muscle hypertonia, stiff knee, and circumduction of the leg.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Progressive spastic quadriplegia
MedGen UID:
347944
Concept ID:
C1859736
Finding
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Frequent falls
MedGen UID:
163408
Concept ID:
C0850703
Finding
Hyperargininemia
MedGen UID:
1733308
Concept ID:
C5399765
Finding
An increased amount of arginine levels in the blood.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Reduced erythrocyte arginase activity
MedGen UID:
1052059
Concept ID:
CN375674
Finding
Activity or concentration of arginase (EC 3.5.3.1) in red blood cells below the lower limit of normal. Arginase catalyzes the last step of the urea cycle.

Professional guidelines

PubMed

Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Adam S, Almeida MF, Assoun M, Baruteau J, Bernabei SM, Bigot S, Champion H, Daly A, Dassy M, Dawson S, Dixon M, Dokoupil K, Dubois S, Dunlop C, Evans S, Eyskens F, Faria A, Favre E, Ferguson C, Goncalves C, Gribben J, Heddrich-Ellerbrok M, Jankowski C, Janssen-Regelink R, Jouault C, Laguerre C, Le Verge S, Link R, Lowry S, Luyten K, Macdonald A, Maritz C, McDowell S, Meyer U, Micciche A, Robert M, Robertson LV, Rocha JC, Rohde C, Saruggia I, Sjoqvist E, Stafford J, Terry A, Thom R, Vande Kerckhove K, van Rijn M, van Teeffelen-Heithoff A, Wegberg Av, van Wyk K, Vasconcelos C, Vestergaard H, Webster D, White FJ, Wildgoose J, Zweers H
Mol Genet Metab 2013 Dec;110(4):439-45. Epub 2013 Sep 12 doi: 10.1016/j.ymgme.2013.09.003. PMID: 24113687
Häberle J, Koch HG
Prenat Diagn 2004 May;24(5):378-83. doi: 10.1002/pd.884. PMID: 15164414

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Increased Arginine] Argininemia, 2022

American College of Medical Genetics and Genomics, Arginine Elevated Algorithm, 2022

American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Arginase Deficiency (argininemia, hyperargininemia, ARG1 deficiency), Urea Cycle Disorder, 2012

Recent clinical studies

Etiology

Teive HAG, Camargo CHF, Pereira ER, Coutinho L, Munhoz RP
Neurogenetics 2022 Jul;23(3):167-177. Epub 2022 Apr 9 doi: 10.1007/s10048-022-00688-3. PMID: 35397036
Angarita SAK, Truong B, Khoja S, Nitzahn M, Rajbhandari AK, Zhuravka I, Duarte S, Lin MG, Lam AK, Cederbaum SD, Lipshutz GS
Mol Genet Metab 2018 Jun;124(2):114-123. Epub 2018 Apr 21 doi: 10.1016/j.ymgme.2018.04.005. PMID: 29724658Free PMC Article
Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium
J Inherit Metab Dis 2018 Jul;41(4):657-667. Epub 2018 Feb 8 doi: 10.1007/s10545-017-0132-5. PMID: 29423830Free PMC Article
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW, Georgiou G; Members of Urea Cycle Disorders Consortium, Lee BH
Hum Mol Genet 2015 Nov 15;24(22):6417-27. Epub 2015 Sep 10 doi: 10.1093/hmg/ddv352. PMID: 26358771Free PMC Article

Diagnosis

Pavuluri H, Jose M, Fasaludeen A, Sundaram S, Radhakrishnan A, Banerjee M, Menon RN
Epileptic Disord 2023 Aug;25(4):556-561. Epub 2023 May 31 doi: 10.1002/epd2.20081. PMID: 37243436
Teive HAG, Camargo CHF, Pereira ER, Coutinho L, Munhoz RP
Neurogenetics 2022 Jul;23(3):167-177. Epub 2022 Apr 9 doi: 10.1007/s10048-022-00688-3. PMID: 35397036
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Christopher R, Rajivnath V, Shetty KT
Indian J Pediatr 1997 Mar-Apr;64(2):266-9. doi: 10.1007/BF02752462. PMID: 10771848
Cederbaum SD, Shaw KN, Valente M
J Pediatr 1977 Apr;90(4):569-73. doi: 10.1016/s0022-3476(77)80368-5. PMID: 839368

Therapy

Pavuluri H, Jose M, Fasaludeen A, Sundaram S, Radhakrishnan A, Banerjee M, Menon RN
Epileptic Disord 2023 Aug;25(4):556-561. Epub 2023 May 31 doi: 10.1002/epd2.20081. PMID: 37243436
Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW, Georgiou G; Members of Urea Cycle Disorders Consortium, Lee BH
Hum Mol Genet 2015 Nov 15;24(22):6417-27. Epub 2015 Sep 10 doi: 10.1093/hmg/ddv352. PMID: 26358771Free PMC Article
Tsang JP, Poon WL, Luk HM, Fung CW, Ching CK, Mak CM, Lam CW, Siu TS, Tam S, Wong VC
Pediatr Neurol 2012 Oct;47(4):263-9. doi: 10.1016/j.pediatrneurol.2012.06.012. PMID: 22964440
Adam S, Champion H, Daly A, Dawson S, Dixon M, Dunlop C, Eardley J, Evans S, Ferguson C, Jankowski C, Lowry S, MacDonald A, Maritz C, Micciche A, Robertson L, Stafford J, Terry A, Thom R, van Wyk K, Webster D, White FJ, Wildgoose J; British Inherited Metabolic Diseases Group (BIMDG) Dietitian’s Group
J Hum Nutr Diet 2012 Aug;25(4):398-404. Epub 2012 May 18 doi: 10.1111/j.1365-277X.2012.01259.x. PMID: 22594780
Snyderman SE, Sansaricq C, Chen WJ, Norton PM, Phansalkar SV
J Pediatr 1977 Apr;90(4):563-8. doi: 10.1016/s0022-3476(77)80367-3. PMID: 839367

Prognosis

Pavuluri H, Jose M, Fasaludeen A, Sundaram S, Radhakrishnan A, Banerjee M, Menon RN
Epileptic Disord 2023 Aug;25(4):556-561. Epub 2023 May 31 doi: 10.1002/epd2.20081. PMID: 37243436
Kido J, Matsumoto S, Häberle J, Nakajima Y, Wada Y, Mochizuki N, Murayama K, Lee T, Mochizuki H, Watanabe Y, Horikawa R, Kasahara M, Nakamura K
J Inherit Metab Dis 2021 Jul;44(4):826-837. Epub 2021 Apr 18 doi: 10.1002/jimd.12384. PMID: 33840128
Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium
J Inherit Metab Dis 2018 Jul;41(4):657-667. Epub 2018 Feb 8 doi: 10.1007/s10545-017-0132-5. PMID: 29423830Free PMC Article
Crombez EA, Cederbaum SD
Mol Genet Metab 2005 Mar;84(3):243-51. Epub 2004 Dec 19 doi: 10.1016/j.ymgme.2004.11.004. PMID: 15694174
Grody WW, Kern RM, Klein D, Dodson AE, Wissman PB, Barsky SH, Cederbaum SD
Hum Genet 1993 Mar;91(1):1-5. doi: 10.1007/BF00230212. PMID: 8454280

Clinical prediction guides

Pavuluri H, Jose M, Fasaludeen A, Sundaram S, Radhakrishnan A, Banerjee M, Menon RN
Epileptic Disord 2023 Aug;25(4):556-561. Epub 2023 May 31 doi: 10.1002/epd2.20081. PMID: 37243436
Atemin S, Todorov T, Tourtourikov I, Ivanova MB, Chamova T, Avdjieva-Tzavella D, Kathom H, Georgieva B, Guergueltcheva V, Savov IBA, Tournev I, Mitev V, Todorova A
J Genet 2023;102 PMID: 36722221
Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium
J Inherit Metab Dis 2018 Jul;41(4):657-667. Epub 2018 Feb 8 doi: 10.1007/s10545-017-0132-5. PMID: 29423830Free PMC Article
Saudubray JM, Rabier D
J Nutr 2007 Jun;137(6 Suppl 2):1669S-1672S. doi: 10.1093/jn/137.6.1669S. PMID: 17513445
Grody WW, Kern RM, Klein D, Dodson AE, Wissman PB, Barsky SH, Cederbaum SD
Hum Genet 1993 Mar;91(1):1-5. doi: 10.1007/BF00230212. PMID: 8454280

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, Argininemia 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Increased Arginine] Argininemia, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Arginine Elevated Algorithm, 2022
    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Arginase Deficiency (argininemia, hyperargininemia, ARG1 deficiency), Urea Cycle Disorder, 2012

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